Method of treating bendamustine-responsive conditions in patients requiring reduced volumes for administration

ABSTRACT

Methods of treating bendamustine responsive conditions in patients having fluid and/or sodium intake restrictions are disclosed. The methods include identifying patients having such restrictions and in need of bendamustine, and then administering thereto a bendamustine-containing composition in a volume of about 120 ml or less intravenously over a period of about 15 minutes or less. The smaller volumes and reduced sodium load as compared to currently known methods of treatment minimize cardiac and/or renal stress in patients having diseases such as congestive heart failure or renal disease.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority from U.S. ProvisionalPatent Application Ser. No. 61/613,173, filed Mar. 20, 2012, 61/669,889,filed Jul. 10, 2012, and 61/678,715, filed Aug. 2, 2012, the disclosureof which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

Bendamustine is used in the treatment of a number of cancers includingleukemias, Hodgkin's disease and multiple myelomas. Bendamustine,(present as the HCl salt) is the active ingredient of the commercialproduct Treanda™, a lyophilized powder for reconstitution. Currentlabeling requirements call for the reconstituted product to beimmediately (within 30 minutes) diluted into 500 mL of parenterallyacceptable diluents such as 0.9% saline (normal saline) or 2.5%dextrose/0.45% saline and administered as part of an intravenousinfusion delivering 100 mg/m² over 30 minutes or 120 mg/m² over 60minutes. The diluted admixture may be stored at 2-8° C. for up to 24hours, or 3 hours at room temperature (15-30° C.); administration mustbe completed within this period due to limited chemical stability inaqueous solutions.

Higher infusion volume and longer infusion times, however, areassociated with many drawbacks. For example, currently availablebendamustine therapies with their larger intravenous administrationvolumes and sodium loads can be contraindicated in patients who havesignificant cardiac disease such as congestive heart failure and/orrenal failure. Thus, some patients who would benefit from bendamustinetherapy cannot take the drug or, if there are no alternative therapies,are exposed to significant physical harm as a result of receiving largevolumes of sodium-containing fluid along with the bendamustine. Thehigher infusion volumes cause unhealthy stress on diseased organsincluding the heart and kidney in these patients. It would be mostadvantageous if the drug could be administered in smaller volumes andover shorter times to patients needing the drug but also requiring fluidand sodium intake restrictions. The present invention addresses thisneed.

SUMMARY OF THE INVENTION

In a first aspect of the invention there are provided methods oftreating a bendamustine-responsive condition in a subject requiringrestricted fluid and/or sodium intake. The methods include

a) identifying a subject in need of bendamustine therapy and having aphysiological condition requiring restricted fluid and/or sodium intake;

b) parenterally administering to the subject patient a volume of about120 ml or less of a liquid composition containing:

-   -   i) from about 0.05 to about 12.5 mg/ml of bendamustine or a        pharmaceutically acceptable salt thereof;    -   ii) a solubilizer comprising polyethylene glycol and propylene        glycol, the polyethylene glycol being present in an amount of        from about 0.3 to about to 45% volume and the propylene glycol        being present in an amount of from about 0.03 to about 5%        volume; and, optionally    -   iii) a parenterally acceptable diluent,        over a substantially continuous period of less than or equal to        about 30 minutes.

In alternative aspects of the invention, the methods are similar to thatmentioned above, but the liquid compositions administered contain:

Ingredient Concentration Range (mg/ml) Bendamustine HCl 0.05 to 1.6 Solubilizer 1 propylene glycol 0.3 to 6.5 Solubilizer 2 PEG 400 3.3 to65  Monothioglycerol 0.02 to 0.35 NaOH  0.0 to 0.01

Ingredient Concentration Range (mg/ml) Bendamustine HCl  1.1 to 12.5Solubilizer 1 propylene glycol 4.5 to 51  Solubilizer 2 PEG 400  45 to500 Monothioglycerol 0.2 to 2.5 NaOH   0.0 to 0.04.

As was the case with the first aspect, the compositions administered canoptionally include a parenterally acceptable diluent such as 0.9% NaCl,i.e. normal saline, or 0.45% NaCl. The time period during which theformulation is administered is preferably less than or equal to about 30minutes but can be as brief as about 5 minutes or less, for example,when bolus doses of smaller volumes are administered.

The methods of the present invention take advantage of the fact that theconcentration of the bendamustine HCl is below the room temperaturesolubility limit of the vehicle into which it is placed. As a result,the bendamustine does not precipitate during administration to thepatient. This is advantageous because the enhanced solubility of thedrug allows it to be administered in much smaller volumes than thestandard 500 ml administration volume. Patients with medical conditionsbenefiting from reduced sodium and/or fluid intake can have bendamustinetherapy without the NaCl load associated with a typical 500 ml normalsaline diluent. In fact, the methods of the present invention allow thediluent volume to be reduced by at least 80% (100 ml vs. 500 ml) or morein view volumes being as low as about 15 ml or less. Commensuratereductions in sodium necessarily occur by virtue of the smaller volumesadministered.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art to which this invention belongs. In the event that there is aplurality of definitions for a term herein, those in this sectionprevail unless stated otherwise.

In accordance with a first aspect of the invention there are providedmethods of treating conditions responsive to bendamustine treatment inpatients, preferably humans, requiring such treatment and furtherrequiring or benefiting from restricted fluid and/or sodium intake.Without limiting the scope of the invention, treatments which are knownto be responsive to bendamustine therapy include cancer or malignantdisease generally and more specifically, chronic lymphocytic leukemia(CLL), indolent B-cell non-Hodgkin's lymphoma, Hodgkin's disease,multiple myelomas as well as other conditions know to those of ordinaryskill as being responsive to bendamustine therapy. For purposes of thepresent invention, the step of selecting of patients or subjectssuitable for inclusion in the inventive methods shall be understood tobe one of medical or clinical assessment which involves determination ofthe physical unsuitability of receiving excessive fluid volumes and/orsodium due to congestive heart failure, renal impairment or otherclinical indicia readily apparent to those of ordinary skill.

The methods include

a) identifying and/or selecting a subject, e.g. a human patient, who isin need of both bendamustine therapy and who has or who would benefitfrom one or more of fluid and/or sodium intake restrictions; and

b) parenterally administering to the subject, preferably by theintravenous route and as a single dose, a volume of about 120 ml or lessof a liquid bendamustine-containing composition which contains:

-   -   i) from about 0.05 to about 12.5 mg/ml of bendamustine or a        pharmaceutically acceptable salt thereof;    -   ii) a solubilizer comprising polyethylene glycol and propylene        glycol, the polyethylene glycol being present in an amount of        from about 0.3 to about to 45% volume and the propylene glycol        being present in an amount of from about 0.03 to about 5%        volume; and, optionally    -   iii) a parenterally acceptable diluent,        over a substantially continuous period of less than or equal to        about 30 minutes.

The solubilizer portion of the formulation preferably includes fromabout 0.3 to about 45% volume polyethylene glycol (PEG) and from about0.03 to about 5% volume propylene glycol (PG), as calculated on thebasis of the total or final volume administered. Stated alternatively,the final concentration of the PEG generally ranges from about 3 toabout 500 mg/ml, while the final concentration of the PG generallyranges from about 0.5 to about 51 mg/ml. Within these general ranges,certain aspects of the invention include concentration ranges for thePEG of from about 45 to about 500 mg/ml or from about 3.3 to about 63.3mg/ml. The PG will range of from about 4.7 to about 50.6 mg/ml; or fromabout 0.02 to about 6.5 mg/ml.

The solubilizer is preferably a mixture of polyethylene glycol,hereinafter “PEG” and propylene glycol, hereinafter “PG”. Thesolubilizer can also optionally include an antioxidant such asmonothioglycerol. The amount of antioxidant included is a formulationstabilizing amount, which, in the case of monothioglycerol ranges fromabout 2 to about 10 mg/ml. The PEG preferably has a molecular weight ofabout 400, i.e. PEG 400. Other molecular weight PEG's known to those ofordinary skill can be included if desired in alternative embodiments.

Certain aspects of the invention call for the ratio of the PEG to PGfound in the solubilizer to be about 90:10. In alternative aspects, theratio of the PEG to PG is about 85:15.

In some aspects of the invention, the total amount of solubilizer, i.e.blend of PEG and PG, included in infusion volumes of about 100-115 ml isfrom about 0.5 to about 26.5% vol.; while solubilizer amounts of fromabout 2.0 to about 22.4% vol. included in infusion volumes of about50-65 ml.

Since the solubilizer is a blend, the amount of PEG and PG in variousvolumes (calculated as % vol.) can be as follows:

Solubilizer 50 ml 100 ml PEG 20.12 11.33 PG 2.24   1.26.

In some aspects of the invention, the bendamustine is administeredintravenously as part of an intravenous infusion. Contemplated infusionvolumes are preferably less than 120 ml with volumes such as about 100ml, 50 ml, 30 ml, 15 ml or less, with each volume varying about +/−10%or +/−15% being preferred in some embodiments. In alternative aspects ofthe invention, the intravenous administration volume is suitable for IVbolus administration and may also include an amount of pharmaceuticallyacceptable diluent such as normal saline or one of the other diluentsdescribed herein which does not cause the solubility of the vehicle tofall below the concentration of the bendamustine. Stated alternatively,the final concentration of the bendamustine will be below the solubilityof the combination vehicle containing the mixture of propylene glycoland PEG and diluent. As such, smaller volumes are required to delivertherapeutic doses to patients and the patients are spared exposure toexcess fluid and sodium during therapy.

While most aspects of the invention are described in the context ofadministering less than about 120 ml including all vehicle ingredients,excipients, etc., it should be appreciated that volumes as low as a fewmilliliters, e.g. about 2, can be used so long as the vehicle includessufficient solubilizers to preserve the solubility of the bendamustinetherein during administration to the patient.

For purposes of the present invention, the word “about” when used tomodify infusion volumes or concentrations shall be understood to includevalues which may vary by amounts of about +/−10% or 15%.

In certain embodiments where the infusion volume is about 50 ml, theconcentration of the bendamustine HCl or other pharmaceuticallyacceptable salt thereof is preferably from about 0.5 to about 5.6 mg/ml.In embodiments where the infusion volume is about 100 ml, theconcentration of the bendamustine HCl or other pharmaceuticallyacceptable salt thereof can be preferably from about 0.1 to about 3.2mg/ml.

The bendamustine compositions are preferably infused intravenously overa time period of about 10 minutes or less when the volume is about 50ml; and over a time period of about 15 minutes or less when theintravenous infusion volume is about 100 ml. Shorter time periods arecontemplated for volumes below 50 ml, i.e. 2, 5, 10 or 15 to 30 ml whereIV bolus or IV push administration is used.

The infusible compositions in many aspects of the invention will alsopreferably include the parenterally acceptable diluents such as 0.9%saline (normal saline, preferred), 0.45% saline (half normal saline,also preferred) or 2.5% dextrose/0.45% saline. Alternative diluents suchas water for injection (WFI) are also contemplated.

Formulations well suited for carrying out the methods described hereinare also described in commonly assigned U.S. patent application Ser. No.13/016,473, filed Jan. 28, 2011, and U.S. Ser. No. 13/767,672 filed Feb.14, 2013, the contents of which are incorporated herein by reference. Asreviewed in the '672 patent application, some preferred bendamustineformulations can also include a minor amount of a pH adjuster such assodium formate, sodium phosphate, potassium hydroxide, phosphoric acidor, preferably, sodium hydroxide. Preferably, the amount of sodiumincluded as part of the once daily administration is less than or equalto about 8-16 meq's of sodium per 100 ml administration and less than orequal to about 4-8 meq's of sodium per 50 ml administration. Thetreatments of the present invention therefore provide a significantreduction in sodium intake as compared to currently available treatmentswhich deliver 40-80 meq's of sodium as part of every larger volumeinfusion needed to deliver the same amount of bendamustine.

In an alternative embodiment of the invention, the bendamustineformulations used in the methods described herein can be one or more ofthose described in U.S. Pat. Nos. 8,344,006 and 8,076,366; and US PatentApplication Nos. 2013/0041004; 2012/0071532; 2010/0216858; 2006/0159713;and 2013/0041003, the contents of each of which are incorporated hereinby reference. It being understood that the vehicle into which thebendamustine HCl is placed will have sufficient bendamustine solubilitywhich exceeds the concentration of the drug included therein.

If desired, a sufficient amount of a concentrated, ready to use liquidformulation such one containing 25 mg/ml bendamustine HCl and alreadyadmixed with sufficient solubilizers can be transferred to a suitablefixed volume diluent container such as a bag containing 50 or 100 mlnormal saline or the like. Alternatively, lyophilized bendamustine HClcan be reconstituted, combined with sufficient solubilizer blends asdescribed herein and administered in accordance with the inventivemethods. In such embodiments, the actual amount delivered to the patientwill be slightly more than the diluent amount so as to allow for theaddition of the drug/solubilizer vehicle.

Without limitation, patients in need of both bendamustine therapy andrestricted fluid and/or sodium intake include: a) patients sufferingfrom congestive heart failure (CHF) disease; the disease can be of themild, moderate to severe type CHF; b) patients suffering from any numberof renal diseases in which fluid restrictions are mandated or desirable,including temporary (acute) or chronic renal suppression or renalinsufficiency, acute or chronic kidney failure, etc.

Those aspects of the invention related to treatment of patients havingrenal disease or a predisposition toward renal suppression with lowerinfusion volumes have significant therapeutic benefits as compared tocurrently approved treatments requiring larger infusion volumes. Forexample, elderly lymphoma patients are predisposed to renal difficultiesdue to their age and disease. They are often likely to develop renaldifficulties subsequent to treatment initiation if the condition is notpresent prior to the start of therapy. Acute renal failure is an adverseeffect already recognized as being associated with current treatments,often occurring during the first or second cycles. Many of thosepatients who do not present with acute renal failure nonetheless sufferfrom some form of renal suppression. Consequently, deliveringbendamustine in accordance with the methods of the present inventionwill significantly lessen the incidence of renal injury in patientsrequiring treatment for a bendamustine-treatable condition. The methodsdescribed herein thus offer an alternative when standard volume, i.e.500 ml, infusions of bendamustine is contraindicated.

In some preferred aspects of the invention, methods of treating orpreventing chronic lymphocytic leukemia (CLL) in a patient having fluidand/or sodium intake restrictions are provided. The patient requiringsuch treatment is identified and administered within a time period ofabout 30 minutes or less, a therapeutic amount of bendamustine in avolume of 120 ml or less and a sufficient amount of a solubilizermixture as described herein e.g. from about 0.2 to 27% vol. of asolubilizer comprising polyethylene glycol and propylene glycol; and, ifdesirable, a parenterally acceptable diluent.

The small volume infusions described herein, e.g. 50 or 100 ml solutionscontaining therapeutically effective amounts of bendamustine HCl, can begiven as part of any CLL treatment protocol in which bendamustine isincluded. Thus, the compositions described herein can be administered aspart of a poly-pharmaceutical treatment regimen according to knownprotocols with the exception that the concentrated bendamustinecompositions described herein are administered in smaller infusionvolumes over significantly shorter administration periods than thosecurrently used. For example, some CLL treatment regimens can includeadministering the compositions described herein intravenously as part ofabout 100 ml infusions in about 15 minutes or less on days 1 and 2 of a28 day cycle and repeating the cycle up to 6 times, or longer ifclinically appropriate. If 50 ml volumes are used to deliver thebendamustine, the time of administration is preferably about 10 minutesor less. In spite of the smaller volumes, the amount of bendamustine HCladministered to the patient in need thereof per dose (infusion) in somepreferred embodiments is about 100 mg/m². In some alternative aspects ofthe invention, the amount of bendamustine HCl administered to thepatient in need thereof as part of the 50 or 100 ml infusion is anamount sufficient to provide a dosage of 50 or 25 mg/m². Additionaladministration dosages will be apparent to those of ordinary skill basedupon clinical experience, patient need without undue experimentation.

In another aspect of the invention, methods of treating or preventingthe malignant disease of indolent B-cell non-Hodgkin's lymphoma in apatient having fluid and/or sodium intake restrictions are provided.Similar to the above-mentioned therapy, a patient requiring suchtreatment is identified and a small volume bendamustine-containingcomposition is administered thereto over a period of 15 minutes or less.

More specifically, the bendamustine-containing composition can beadministered intravenously as a 100 ml infusion in about 15 minutes orless on days 1 and 2 of a 21 day cycle for up to 8 cycles, or longer ifclinically appropriate. If 50 ml volumes are used to deliver thebendamustine, the time of administration is preferably about 10 minutesor less. The amount of bendamustine administered to the subject ispreferably about 120 mg/m², although in alternative embodiments, theamount administered can be about 90 or 60 mg/m².

It will be appreciated by those skilled in the art that theabove-mentioned dosages calculated in mg/m² for purposes of body surfacearea (BSA) are consistent with the bendamustine HCl concentrations alsodescribed herein, e.g. 0.5 to 5.6 mg/ml.

In an alternative aspect of the invention, the methods treating abendamustine-responsive condition in subjects requiring restricted fluidand/or sodium intake include

a) identifying a subject in need of bendamustine therapy and having aphysiological condition requiring restricted fluid and/or sodium intake;

b) parenterally administering to said subject a volume of about 120 mlor less of a liquid composition containing:

Ingredient Concentration Range (mg/ml) Bendamustine HCl 0.05 to 1.6 Solubilizer 1 propylene glycol 0.3 to 6.5 Solubilizer 2 PEG 400 3.3 to65  Monothioglycerol 0.02 to 0.35 NaOH  0.0 to 0.01and, optionally a parenterally acceptable diluent, over a substantiallycontinuous period of less than or equal to about 30 minutes. Morepreferably, the administration time is well below 30 minutes and theadministration time will decrease as the volume administered decreases.

Bendamustine formulations containing the above ingredients are capableof delivering approximately 25 mg of the drug as the HCl salt in volumesof pharmaceutically acceptable diluent ranging from about 120 ml down toabout 15 ml. For example, 1 ml of a bendamustine HCl ready to use liquidavailable from Eagle Pharmaceuticals containing

Ingredient Concentration (mg/ml) Bendamustine HCl 25 PG 103.2 PEG 4001013.4 Monothioglycerol 5 NaOH 0.08is combined with 100 ml of a normal saline diluent to provide a final IVinfusion containing 101 ml and a bendamustine final concentration of0.25 mg/ml.

One ml of the 25 mg/ml Eagle bendamustine HCl is diluted into additionaldiluent volumes as shown below:

Diluent Volume Final Volume Final Bendamustine (ml) (ml) Conc. (mg/ml)50 51 0.49 30 31 0.81 15 16  1.56.

The measured solubility of the bendamustine HCl in thediluent/solubilizer combination (50 ml diluent+1 ml of 25 mg/mlbendamustine HCl and solubilizers, etc.) at room temperature was 10.5mg/ml using normal saline and 14.2 mg/ml using half normalsaline/dextrose. The solubility of the diluent/solubilizer combinationfar exceeded the bendamustine concentration, thus assuring the avoidanceof precipitated drug prior to or during administration. As will beappreciated by those of ordinary skill, as the concentration ofsolubilizers increases with respect to the total volume in smalladministration doses, the solubility of the bendamustine is maintained.

In a related embodiment of this aspect of the invention, the methodsinclude treating a bendamustine-responsive condition in a subjectrequiring restricted fluid and/or sodium intake, by

a) identifying a subject in need of bendamustine therapy and having aphysiological condition requiring restricted fluid and/or sodium intake;

b) parenterally administering to said subject a volume of about 120 mlor less of a liquid composition containing:

Ingredient Concentration Range (mg/ml) Bendamustine HCl  1.1 to 12.5Solubilizer 1 propylene glycol 4.5 to 51  Solubilizer 2 PEG 400  45 to500 Monothioglycerol 0.2 to 2.5 NaOH  0.0 to 0.04and, optionally a parenterally acceptable diluent, over a substantiallycontinuous period of less than or equal to about 30 minutes. As was thecase above, the administration time will decrease with the decrease involume administered.

Bendamustine formulations containing the above ingredients are capableof delivering approximately 360 mg of the drug as the HCl salt involumes of pharmaceutically acceptable diluent ranging from about 120 mldown to about 15 ml. As was the case above, the measured solubility ofthe bendamustine HCl in the diluent/solubilizer combination (1 mldrug+solubilizers, etc. and 50 ml diluent) at room temperature was 10.5mg/ml using normal saline and 14.2 mg/ml using half normalsaline/dextrose.

Instead of using only 1 ml of the above described Eagle 25 mg/mlbendamustine HCl ready to use liquid, 14.4 ml is combined with variousamounts of diluent.

Diluent Volume Final Volume Final Bendamustine (ml) (ml) Conc. (mg/ml)100 114.4 3.15 50 64.4 5.59 30 44.4 8.11 15 29.4 12.24

In each case, the solubility of the diluent/solubilizer combinationexceeds the bendamustine concentration, thus assuring the avoidance ofprecipitated drug prior to or during administration.

EXAMPLES

The following examples serve to provide further appreciation of theinvention but are not meant in any way to restrict the effective scopeof the invention.

Example 1

In this example, a patient diagnosed with chronic lymphocytic leukemia(CLL) and having chronic kidney disease (GFR<30 ml/min/1.73 m²) is begunon a treatment protocol with bendamustine. In particular, the patient isadministered 360 mg of bendamustine as part of an approximately 114.4 mlinfusion on days 1 and 2 of a 28 day cycle. The intravenous formulationis prepared by drawing up 14.4 ml of an RTU (ready to use) liquidcontaining bendamustine HCl 25 mg/ml, PG 103.2 mg/ml, PEG 1013.4 mg/ml,monothioglycerol 5 mg/ml and 0.08 mg/ml NaOH and mixing it into a 100 mlbag containing 0.9% NaCl. The final bendamustine concentration for theIV fluid is 3.15 mg/ml. The infusion is administered to the patient inless than 15 minutes. No precipitated bendamustine is observed in the IVfluid during administration.

Example 2

The process of Example 1 is repeated except that the IV infusion volumeis approximately 64.4 ml. The same 14.4 ml of an RTU (ready to use)liquid containing bendamustine HCl 25 mg/ml, PG 103.2 mg/ml, PEG 1013.4mg/ml, monothioglycerol 5 mg/ml and 0.08 mg/ml NaOH is used and it ismixed into a 50 ml bag containing 0.9% NaCl. The final bendamustineconcentration for the IV fluid is 5.59 mg/ml. The infusion isadministered to the patient in less than 10 minutes. No precipitatedbendamustine is observed in the IV fluid during administration.

Example 3

In this Example, the process of Example 1 is repeated except thatlyophilized bendamustine HCl is reconstituted with a solubilizer mixturecontaining PEG:PG (90:10) before dilution into the 100 ml bag containingnormal saline.

We claim:
 1. A method of treating a bendamustine-responsive condition ina subject requiring restricted fluid and/or sodium intake, comprising a)identifying a subject in need of bendamustine therapy and having aphysiological condition requiring restricted fluid and/or sodium intake;b) parenterally administering to said subject a volume of about 100 mlor less of a liquid composition containing: i) from about 0.05 to about12.5 mg/ml of bendamustine or a pharmaceutically acceptable saltthereof; ii) a solubilizer comprising polyethylene glycol and propyleneglycol, the polyethylene glycol being present in an amount of from about0.3 to about to 45% volume and the propylene glycol being present in anamount of from about 0.03 to about 5% volume; and, optionally iii) aparenterally acceptable diluent over a substantially continuous periodof less than or equal to about 30 minutes.
 2. The method of claim 1,wherein the diluent comprises 0.9% NaCl or 0.45% NaCl.
 3. The method ofclaim 1, wherein the subject has congestive heart disease.
 4. The methodof claim 1, wherein the subject has renal insufficiency.
 5. The methodof claim 4, wherein the renal insufficiency is renal failure or renalsuppression.
 6. The method of claim 1, wherein the concentration of thebendamustine or pharmaceutically acceptable salt is from about 0.1 toabout 3.2 mg/ml.
 7. The method of claim 1, wherein the concentration ofthe bendamustine or pharmaceutically acceptable salt is from about 0.5to about 5.6 mg/ml.
 8. The method of claim 1, wherein the amount ofsolubilizer is from about 0.5 to about 26.5% vol.
 9. The method of claim1, wherein the amount of solubilizer is from about 2.0 to about 22.4%vol.
 10. The method of claim 1, where the polyethylene glycol is PEG400.
 11. The method of claim 1, wherein the weight ratio of polyethyleneglycol to propylene glycol is about 90:10.
 12. The method of claim 1,wherein the weight ratio of polyethylene glycol to propylene glycol isabout 85:15.
 13. The method of claim 1, wherein the volume administeredis about 50, 30 or 15 ml.
 14. The method of claim 1, wherein thecomposition further comprises monothioglycerol and NaOH.
 15. The methodof claim 7, wherein the volume administered is about 50 ml+/−15% or lessand the composition is administered over a time period of about 10minutes or less.
 16. The method of claim 6, wherein the volumeadministered is about 100 ml+/−15% or less and the composition isadministered over a time period of about 15 minutes or less.
 17. Themethod of claim 1, wherein the parenterally acceptable diluent is 0.9%NaCl (normal saline).
 18. The method of claim 1, wherein thebendamustine-responsive condition is chronic lymphocytic leukemia. 19.The method of claim 18, wherein the composition is administeredintravenously in a volume of about 50 ml over a time period of about 10minutes or less on days 1 and 2 of a 28 day cycle.
 20. The method ofclaim 18, wherein the composition is administered intravenously in avolume of about 100 ml over a time period of about 15 minutes or less ondays 1 and 2 of a 28 day cycle.
 21. The method of claim 18, wherein thecomposition is administered for up to 6 cycles.
 22. The method of claim18, wherein the volume of the composition administered to the subjectprovides a dosage amount ranging from about 25 mg/m² to about 100 mg/m²to the subject.
 23. The method of claim 1, wherein thebendamustine-responsive condition is indolent B-cell non-Hodgkin'slymphoma.
 24. The method of claim 23, wherein the composition isadministered intravenously in a volume of about 50 ml over a time periodof about 10 minutes or less on days 1 and 2 of a 21 day cycle.
 25. Themethod of claim 23, wherein the composition is administeredintravenously in a volume of about 100 ml over a time period of about 15minutes or less on days 1 and 2 of a 21 day cycle.
 26. The method ofclaim 23, wherein the composition is administered for up to 8 cycles.27. The method of claim 23, wherein the volume of the compositionadministered to the subject provides a dosage amount ranging from about60 mg/m² to about 120 mg/m² to the subject.
 28. A method of treating abendamustine-responsive condition in a subject requiring restrictedfluid and/or sodium intake, comprising a) identifying a subject in needof bendamustine therapy and having a physiological condition requiringrestricted fluid and/or sodium intake; b) parenterally administering tosaid subject a volume of about 100 ml or less of a liquid compositioncontaining: Ingredient Concentration Range (mg/ml) Bendamustine HCl 0.05to 1.6  Solubilizer 1 propylene glycol 0.3 to 6.5 Solubilizer 2 PEG 4003.3 to 65  Monothioglycerol 0.02 to 0.35 NaOH  0.0 to 0.01

and, optionally a parenterally acceptable diluent, over a substantiallycontinuous period of less than or equal to about 30 minutes.
 29. Amethod of treating a bendamustine-responsive condition in a subjectrequiring restricted fluid and/or sodium intake, comprising a)identifying a subject in need of bendamustine therapy and having aphysiological condition requiring restricted fluid and/or sodium intake;b) parenterally administering to said subject a volume of about 100 mlor less of a liquid composition containing: Ingredient ConcentrationRange (mg/ml) Bendamustine HCl  1.1 to 12.5 Solubilizer 1 propyleneglycol 4.5 to 51  Solubilizer 2 PEG 400  45 to 500 Monothioglycerol 0.2to 2.5 NaOH  0.0 to 0.04

and, optionally a parenterally acceptable diluent, over a substantiallycontinuous period of less than or equal to about 30 minutes.
 30. Amethod according to claim 1, wherein the bendamustine is present as thehydrochloride salt.